Prostate cancer is the second cause of death in the male population of the western countries. In case of localised cancer, radical prostatectomy and the local radiotherapy have revealed to be efficient while in the case of metastatic prostate carcinoma (PCa), they have unfortunately revealed poor curing properties.
Thus, it is necessary to find alternative therapies for the metastatic prostate cancer refractory to hormone treatments. The success of such approach depends on the ability of the cytotoxic T cells to eliminate the tumour cells. However, should the tumour environment exert a suppressive action on the action of the antigen-specific tumour-infiltrating lymphocytes (TIL), the immunotherapy has poor success.
Thus, understanding the biology of the TIL cells and the modulation of the response thereof by the tumour is of fundamental importance.
The role of the prostatic tumour environment in the modulation of the response of the T cells was analysed by using culture of human PCa on a collagen matrix. This technique offers the advantage of maintaining the microenvironment intact, as well as all the factors that can influence the activity of the TIL cells, such as the cell-cell interaction or interaction between a cell attached to the matrix and the interstitial fluid. This new approach has allowed to obtain considerable results. Generally, the TIL in the PCa samples are mainly differentiated T CD8+ (CD8+, CF45RA+, CD62L− and CCR7−) and perforin positive lymphocytes, and thus potentially capable of eliminating the cancerous cells. However, the latter are in dormant state, given that they do not express activation markers as CD25, CD69 and CD137. Furthermore, contrary to the lymphocytes present in non-tumour prostate tissues and in the peripheral blood, the TILs have no response to activation signals which act either on the TCR or downstream signal pathways, indicating a deficiency restricted to the tumour. Additionally, there has been extensive evidence that the arginase enzymes (ARG) and NO-synthase (NOS) are overexpressed in PCa if compared to the hyperplasic prostate, with the interesting observation revealing that actually the tumour cells and not the infiltrating myeloid cells, could be the main source of enzymes. The results indicate that the steady-state regulation of the dormant state of the TIL depends on the increased intratumoral metabolism of the L-arginine amino acid (L-Arg), given that the simple addition of specific ARGs and NOS inhibitor was sufficient to arouse the CTLs, activate them and start a series of events that lead to the cytolytic polarisation of the granules and to the elimination of the target. In addition, it was also demonstrated that the presence of high levels of nitrotyrosine in the TIL, which suggests of the local production of peroxynitrite, is possibly due to the activity of ARG and NOS, given that inhibiting the activity of the enzymes also lead to reduced tyrosine nitration.
These results identify a mechanism through which the human prostate cancer induces immunosuppression in situ. Therefore, active ingredients that control the generation of reactive nitrogen species (RNS) could be useful in the immunotherapeutic approach for the treatment of the cancer, creating a tumour environment favourable for the activation of the lymphocytes (Bronte et al., 2005).
The results of the clinical assays revealed that the efficiency of the different immunotherapeutic approaches is not suitable for an immediate and extensive transfer to the therapeutic treatment on patients.
An important emerging concept is that the altered metabolism present in the tumour microenvironment can have a deep impact on the anti-tumour activity. Considering the previously mentioned results, it is clear that the active ingredients that control the generation of the reactive nitrogen species (RNS) can considerably increase the impact of the immunotherapeutic approaches for the treatment of cancer.
Already known conventional adjuvants, such as the cytokines and activators of the antigen presenting the cells, are characterised by an extensive activity on the immune system, but they lack selectivity and can lead to considerable adverse effects.
Hence, there continuously arises the need of finding novel compounds free of such drawbacks.